Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen–targeted therapies

Samir Zaidi, Jooyoung Park, Joseph M. Chan, Martine P. Roudier, Jimmy L. Zhao, Anuradha Gopalan, Kristine M. Wadosky, Radhika A. Patel, Erolcan Sayar, Wouter R. Karthaus, D. Henry Kates, Ojasvi Chaudhary, Tianhao Xu, Ignas Masilionis, Linas Mazutis, Ronan Chaligné, Aleksandar Obradovic, Irina Linkov, Afsar Barlas, Achim A. JungbluthNatasha Rekhtman, Joachim Silber, Katia Manova-Todorova, Philip A. Watson, Lawrence D. True, Colm Morrissey, Howard I. Scher, Dana E. Rathkopf, Michael J. Morris, David W. Goodrich, Jungmin Choi, Peter S. Nelson, Michael C. Haffner, Charles L. Sawyers

    Research output: Contribution to journalArticlepeer-review

    3 Citations (Scopus)

    Abstract

    Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)—a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

    Original languageEnglish
    Article numbere2322203121
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume121
    Issue number28
    DOIs
    Publication statusPublished - 2024 Jul 9

    Bibliographical note

    Publisher Copyright:
    Copyright © 2024 the Author(s). Published by PNAS.

    Keywords

    • cell states
    • epithelial maligancies
    • heterogeneity
    • lineage plasticity

    ASJC Scopus subject areas

    • General

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